Neural correlates of three types of negative life events during angry face processing in adolescents.

Negative life events (NLE) contribute to anxiety and depression disorders, but their relationship with brain functioning in adolescence has rarely been studied. We hypothesized that neural response to social threat would relate to NLE in the frontal-limbic emotional regions. Participants (N = 685) were drawn from the Imagen database of 14-year-old community adolescents recruited in schools. They underwent functional MRI while viewing angry and neutral faces, as a probe to neural response to social threat. Lifetime NLEs were assessed using the 'distress', 'family' and 'accident' subscales from a life event dimensional questionnaire. Relationships between NLE subscale scores and neural response were investigated. Links of NLE subscales scores with anxiety or depression outcomes at the age of 16 years were also investigated. Lifetime 'distress' positively correlated with ventral-lateral orbitofrontal and temporal cortex activations during angry face processing. 'Distress' scores correlated with the probabilities of meeting criteria for Generalized Anxiety Disorder or Major Depressive Disorder at the age of 16 years. Lifetime 'family' and 'accident' scores did not relate with neural response or follow-up conditions, however. Thus, different types of NLEs differentially predicted neural responses to threat during adolescence, and differentially predicted a de novo internalizing condition 2 years later. The deleterious effect of self-referential NLEs is suggested

Pubertal maturation and sex effects on the default-mode network connectivity implicated in mood dysregulation

This study examines the effects of puberty and sex on the intrinsic functional connectivity (iFC) of brain networks, with a focus on the default-mode network (DMN). Consistently implicated in depressive disorders, the DMN’s function may interact with puberty and sex in the development of these disorders, whose onsets peak in adolescence, and which show strong sex disproportionality (females > males). The main question concerns how the DMN evolves with puberty as a function of sex. These effects are expected to involve within- and between-network iFC, particularly, the salience and the central-executive networks, consistent with the Triple-Network Model. Resting-state scans of an adolescent community sample (n = 304, male/female: 157/147; mean/std age: 14.6/0.41 years), from the IMAGEN database, were analyzed using the AFNI software suite and a data reduction strategy for the effects of puberty and sex. Three midline regions (medial prefrontal, pregenual anterior cingulate, and posterior cingulate), within the DMN and consistently implicated in mood disorders, were selected as seeds. Within- and between-network clusters of the DMN iFC changed with pubertal maturation differently in boys and girls (puberty-X-sex). Specifically, pubertal maturation predicted weaker iFC in girls and stronger iFC in boys. Finally, iFC was stronger in boys than girls independently of puberty. Brain–behavior associations indicated that lower connectivity of the anterior cingulate seed predicted higher internalizing symptoms at 2-year follow-up. In conclusion, weaker iFC of the anterior DMN may signal disconnections among circuits supporting mood regulation, conferring risk for internalizing disorders

Early variations in white matter microstructure and depression outcome in adolescents with subthreshold-depression

Objective: White matter microstructure alterations have recently been associated with adolescence depressive episodes, but it is unknown whether they predate depression. We investigated whether subthreshold-depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome.Method: Adolescents with subthreshold-depression (n=96) and healthy controls (n=336), drawn from a community-based cohort, were compared using diffusion tensor imaging and whole-brain tractbased spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followedup at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines from the TBSS analysis resulting regions, and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. We searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold-depression and depression at follow-up, and then explored the specificity of the findings.Results: Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold-depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between baseline subthreshold-depression and follow-up depression was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression.Conclusions: Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex might denote higher risk of transition to depression in adolescents

Early variations in white matter microstructure and depression outcome in adolescents with subthreshold-depression

Objective: White matter microstructure alterations have recently been associated with adolescence depressive episodes, but it is unknown whether they predate depression. We investigated whether subthreshold-depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome. Method: Adolescents with subthreshold-depression (n=96) and healthy controls (n=336), drawn from a community-based cohort, were compared using diffusion tensor imaging and whole-brain tractbased spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followedup at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines from the TBSS analysis resulting regions, and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. We searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold-depression and depression at follow-up, and then explored the specificity of the findings. Results: Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold-depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between baseline subthreshold-depression and follow-up depression was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression. Conclusions: Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex might denote higher risk of transition to depression in adolescents

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Disentangling pharmacological and expectation effects in antidepressant discontinuation among patients with fully remitted major depressive disorder: study protocol of a randomized, open-hidden discontinuation trial

Abstract Background Antidepressants are established as an evidence-based, guideline-recommended treatment for Major Depressive Disorder. Prescriptions have markedly increased in past decades, with a specific surge in maintenance prescribing. Patients often remain on antidepressants longer than clinically necessary. When attempting to stop, many patients experience adverse discontinuation symptoms. Discontinuation symptoms can be debilitating and hinder successful discontinuation. While discontinuation symptoms can result from pharmacological effects, evidence on nocebo-induced side effects of antidepressant use suggests that patients' expectations may also influence occurrence. Methods To disentangle pharmacological and expectation effects in antidepressant discontinuation, patients with fully remitted Major Depressive Disorder who fulfill German guideline recommendations to discontinue will either remain on or discontinue their antidepressant. Participants' expectations will be manipulated by varying verbal instructions using an open-hidden paradigm. Within the open trial arms, participants will receive full information about treatment, i.e., high expectation. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant, i.e., moderate expectation. A total of N = 196 participants will be randomly assigned to either of the four experimental groups: open discontinuation (OD; n = 49), hidden discontinuation (HD; n = 49), open continuation (OC; n = 49), or hidden continuation (HC; n = 49). Discontinuation symptom load during the 13-week experimental phase will be our primary outcome measure. Secondary outcome measures include discontinuation symptom load during the subsequent 39-week clinical observation phase, recurrence during the 13-week experimental period, recurrence over the course of the complete 52-week trial evaluated in a time-to-event analysis, and stress, anxiety, and participants’ attentional and emotional processing at 13 weeks post-baseline. Blood and saliva samples will be taken as objective markers of antidepressant blood serum level and stress. Optional rsfMRI measurements will be scheduled. Discussion Until today, no study has explored the interplay of pharmacological effects and patients’ expectations during antidepressant discontinuation. Disentangling their effects has important implications for understanding mechanisms underlying adverse discontinuation symptoms. Results can inform strategies to manage discontinuation symptoms and optimize expectations in order to help patients and physicians discontinue antidepressants more safely and effectively. Trial registration ClinicalTrials.gov (NCT05191277), January 13, 2022

The brain’s response to reward anticipation and depression in adolescence: dimensionality, specificity and longitudinal predictions in a community-based sample

International audienceOBJECTIVE: The authors examined whether alterations in the brain's reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes.METHOD: Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally.RESULTS: Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses.CONCLUSIONS: The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria

Identification of neurobehavioural symptom groups based on shared brain mechanisms

International audienceMost psychopathological disorders develop in adolescence. The biological basis for this development is poorly understood. To enhance diagnostic characterization and develop improved targeted interventions, it is critical to identify behavioural symptom groups that share neural substrates. We ran analyses to find relationships between behavioural symptoms and neuroimaging measures of brain structure and function in adolescence. We found two symptom groups, consisting of anxiety/depression and executive dysfunction symptoms, respectively, that correlated with distinct sets of brain regions and inter-regional connections, measured by structural and functional neuroimaging modalities. We found that the neural correlates of these symptom groups were present before behavioural symptoms had developed. These neural correlates showed case-control differences in corresponding psychiatric disorders, depression and attention deficit hyperactivity disorder in independent clinical samples. By characterizing behavioural symptom groups based on shared neural mechanisms, our results provide a framework for developing a classification system for psychiatric illness that is based on quantitative neurobehavioural measures